1. Field of the Invention
This invention relates to a vaccine for respiratory syncytial virus and to a method for producing the vaccine.
Respiratory syncytial virus, discovered in 1956, is worldwide in distribution but unfamiliar to most patients. It is an important cause of respiratory tract illness in infants and young children. In infants this severe illness often requires hospitalization and is considered a cause of sudden infant death syndrome. About 30 percent of hospitalized young children with acute respiratory disease have respiratory syncytial virus infection. In older children and adults the disease is milder. Infections with respiratory syncytial virus are referable to all segments of the respiratory tract, are usually associated with fever, cough, runny nose, and fatigue, and are diagnosed clinically as bronchitis, bronchiolitis, pneumonia, croup, or viral infection. In older children and adults the virus is limited in growth in the upper respiratory tract. Infants may be more severely involved when the virus extends into the lungs.
Primary infection with respiratory syncytial virus occurs early in life, usually before 4 years of age. Among children, illness caused by this virus tends to occur at least once each year in rather sharply defined outbreaks of several months duration. Epidemics are sharply circumscribed, generally for 3 to 5 months. In family studies, children in early school years frequently introduce the virus into the home, infecting younger members of the family more severely than other family members. The clinical consequence of infection is most severe on first experience and becomes milder in older individuals who are immunologically experienced.
The effects of respiratory syncytial virus can range from inapparent infection to severe pneumonia and death. Inflamation of the respiratory track is responsible for most symptoms. Complete recovery in most cases occurs in one to three weeks with the production of protective antibody which appears to persist throughout life. In the United States about 30 percent of 1-year old infants and 95 percent of 5-year old children have circulating respiratory syncytial virus antibody. Reinfections in older infants, children, and adults with antibody are mostly mild upper respiratory illnesses in the form of colds.
2. Description of the Prior Art
Friedewald et al., Journal of the American Medical Association, Vol. 204, 20 May 1968, pp. 690-694 describe the propagation of respiratory syncytial virus in bovine embryonic kidney tissue culture. Virus grown at 34.degree. C. or 28.degree. C. did not decrease in infectivity or virulence. Virus grown at 26.degree. C., however, while associated with a decrease in infectivity for adults, could not be considered for use in prevention of infection in adults since the virus had limited infectivity and was poorly immunogenic. The effect on the young of virus grown at 26.degree. C. was not determined.
Kim et al., Pediatrics, Vol. 48, November 1971, pp. 745-755, disclose that inactivated respiratory syncytial virus vaccine prepared from virus grown at 26.degree. C. stimulated the development of high levels of serum antibody in infants and children from 6 months to 13 years in age but did not prevent infection.
McIntosh et al., Pediatric Research, Vol. 8, 1974, pp. 689-696, discuss two experimental live respiratory syncytial virus vaccines, one prepared from virus grown at 26.degree. C. and the other, prepared from a temperature sensitive mutant which grew well at 32.degree. C. and not at all at 37.degree. C. or higher. The first vaccine was unsatisfactory as it did not protect against infection when the interval between vaccination and challenge was greater than 4 months. The second vaccine was also unsatisfactory in that it apparently lost its temperature sensitivity in some vaccinees.
Craighead, Journal of Infectious Diseases, Vol. 131, June 1975, pp. 749-753, discusses tests conducted in 1966 wherein several groups of investigators tested in infants and young children a formaldehyde-treated, alum-precipitated virus grown in tissue culture. Upon subsequent exposure to wild virus the vaccine recipients exhibited an accentuated pattern of respiratory tract disease. Craighead concludes that immunization enhanced the severity of the disease.
Wright et al., Journal of Pediatrics, Vol. 88, June 1976, pp. 931-936, describe the evaluation in infants of a temperature sensitive live attenuated respiratory syncytial vaccine. While this vaccine when administered at a dosage level sufficiently high to infect all seronegative infants caused mild upper respiratory illness, lowering the dose did not achieve an acceptable level of infectivity. The virus was also genetially unstable as there was evidence of loss of temperature sensitivity in one vaccinee. While there was no evidence for potentiation of natural illness of this vaccine, reinfection occurred among vaccinees.
3. Objects of the Invention
It is, accordingly, an object of the present invention to provide a safe, effective respiratory syncytial virus vaccine. Another object is to provide a respiratory syncytial virus vaccine which is antigenic while non-pathogenic. A further object is to provide a respiratory syncytial virus vaccine which protects against the effects of this virus on both initial and subsequent challenge. Still another object is to provide physiologically acceptable compositions for administering respiratory syncytial virus vaccine. Yet another object is to provide a method for attenuating respiratory syncytial virus. Another object is to provide a method for preparing a respiratory syncytial virus vaccine. These and other objects of the present invention will be apparent from the following description.